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WO-2026096291-A1 - DIAMINOTRIAZOLE DERIVATIVES AS JANUS KINASE 2 INHIBITORS AND USES THEREOF

WO2026096291A1WO 2026096291 A1WO2026096291 A1WO 2026096291A1WO-2026096291-A1

Abstract

There are provided compounds that may act as Janus kinase 2 (JAK2) inhibitors, compositions comprising these compounds and their use in treating cancers such as myeloproliferative neoplasm (MPN). In particular, the compounds are diaminotriazole derivatives capable of binding to the pseudokinase domain (PK or JH2 domain) and to the gain-of-function V617F mutation in the pseudokinase domain of JAK2 that is prevalent in patients with MPN.

Inventors

  • HATCHER, John Michael
  • TEMOTHEO TAVARES, Mauricio
  • CANDIDO PRIMI, Marina
  • ECK, MICHAEL J.

Assignees

  • DANA-FARBER CANCER INSTITUTE, INC.

Dates

Publication Date
20260507
Application Date
20251024
Priority Date
20241028

Claims (20)

  1. 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Ri is -SO2NH2, -CONHCH3 or -CON(CH 3 ) 2 ; R2 is R3 is H; m is 1 or 0; A is a 5- or 6-membered aryl or heteroaryl ring; n is 0, 1, or 2; each Y is independently a halide; Z is selected from the group consisting of -SO2F, -OSO2F or -CHO.
  2. 2. The compound of formula (I) according to claim 1, wherein R2 is: wherein Yi, Y2 and Y 3 are independently H or a halide, preferably Cl, F or H, more preferably H or F.
  3. 3. The compound of formula (I) according to claim 2, wherein R2 is: Atty. Dckt. No. DFCI 3463.W01WO
  4. 4. The compound of formula (I) according to claim 2 or 3, wherein Z is -SO2F or -OSO2F; Yi is H or F; Y2 is H or F; and/or Y3 is H or F; preferably H.
  5. 5. The compound of formula (I) according to claim 2 or 3, wherein Z is -CHO; Yi is F; Y2 is H; and/or Y 3 is F.
  6. 6. The compound of formula (I) according to claim 2, wherein R2 is:
  7. 7. The compound of formula (I) according to claim 6, wherein: Yi is H; Y 2 is H; Y 3 is H; and/or Z is -OSO2F. Atty. Dckt. No. DFCI 3463.W01WO
  8. 8. A compound, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of:
  9. 9. A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein Ri is -SO2NH2, -C(=O)NH(CH3) or -C(=O)N(CH 3 ) 2 ; one of R2 or R3 is H and the other is: Atty. Dckt. No. DFCI 3463.W01WO m is 0 or 1; Xi and X2 are each independently selected from the group consisting of F, Cl, and H; and wherein one of X3 or X4 is H and the other is selected from the group consisting of: wherein n is 0, 1, 2 or 3; wherein p is 0 or 1; or wherein X3 and X4 join together so that R2 or R3 is: Atty. Dckt. No. DFCI 3463.W01WO with the proviso that the following compounds are excluded:
  10. 10. The compound, or a pharmaceutically acceptable salt thereof, according to claim 9, wherein one of X3 or X4 is H and the other is selected from the group consisting of Atty. Dckt. No. DFCI 3463.W01WO preferably and/or preferably wherein Ri is -SO2NH2; and/or preferably wherein each of Xi and X2 is F; and/or preferably wherein m is 0; or wherein X3 and X4 join together so that one of R2 or R3 is: ; preferably wherein each of Xi and X2 H; and/or preferably wherein Ri is -C(=O)NH(CH3) or -C(=O)N(CH3)2; and/or preferably wherein m is 0.
  11. 11. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claim 9 or 10, wherein R2 is H and R3 is: such that the compound of formula (I) forms a compound of formula (II): Atty. Dckt. No. DFCI 3463.W01WO
  12. 12. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claim 9 to 11, wherein R3 is H and R2 is: so that the compound of formula (I) forms a compound of formula (III):
  13. 13. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claim 9 to 12, wherein Ri is -SO2NH2 so that the compound of formula (I) forms a compound of formula (la): Atty. Dckt. No. DFCI 3463.W01WO preferably wherein R3 is H and R2 is: so that the compound of formula (I) forms a compound of formula (Illa):
  14. 14. The compound, or a pharmaceutically acceptable salt thereof, according to any preceding claim, wherein m is 0.
  15. 15. A compound, or a pharmaceutically acceptable salt thereof, according to claim 9, wherein the compound is selected from the group consisting of: Atty. Dckt. No. DFCI 3463.W01WO Atty. Dckt. No. DFCI 3463.W01WO
  16. 16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  17. 17. A method of treating a disease treatable by inhibiting Janus kinase 2 comprising administration to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 15 or pharmaceutically acceptable salt thereof.
  18. 18. A compound according to any one of claims 1 to 15 or pharmaceutically acceptable salt thereof for use in treating a disease, preferably a disease treatable by inhibiting Janus kinase 2.
  19. 19. Use of a compound according to any one of claims 1 to 15 or pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease, preferably a disease treatable by inhibiting Janus kinase 2.
  20. 20. The method, compound for use, or use according to any one of claims 17 to 19, wherein the disease is associated with a V617F mutation in the Janus kinase 2 pseudokinase domain, preferably wherein the disease a myeloproliferative neoplasm (MPN), preferably is selected from the group consisting of chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), polycythemia vera (PV), primary myelofibrosis (PMF; e.g., the prefibrotic stage or the overt fibrotic stage), essential thrombocythemia (ET), chronic eosinophilic leukemia (not otherwise specified), and unclassifiable myeloproliferative neoplasm (MPN-U).

Description

Atty. Dckt. No. DFCI 3463.W01WO DIAMINOTRIAZOLE DERIVATIVES AS JANUS KINASE 2 INHIBITORS AND USES THEREOF Federally Sponsored Research and Development [001] This invention was made with government support under R35 CA242461 awarded by the National Institutes of Health. The government has certain rights in the invention. Field [002] There are provided compounds that may act as Janus kinase 2 (JAK2) inhibitors, compositions comprising these compounds and their use in treating cancers such as myeloproliferative neoplasm (MPN). In particular, the compounds are diaminotriazole derivatives capable of binding to the pseudokinase domain (PK or JH2 domain) and to the gain- of-function V617F mutation in the pseudokinase domain of JAK2 that is prevalent in patients with MPN. Background [003] Janus kinase (JAK) is a family of non-receptor tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that associate with the cytoplasmic tail of cytokine receptors and are involved in signaling networks that regulate and maintain hematopoiesis and the immune responses (Nair et al., Blood Cancer Discov. 2023; 4:352-64). JAKs present four functional domains: band 4.1/ezrin/radixin/moesin (FERM) domain, Src Homology 2-like (SH2-like) domain, and two ATP binding domains, the kinase domain (JH1; JAK2K) and pseudokinase domain (JH2; JAK2PK). The active kinase domain phosphorylates intracellular transcription factors, and the pseudokinase domain negatively regulates the kinase domain’s activity (Baker et al., Oncogene 2007; 26:6724-6737). This tandem (pseudo-)kinase structure is particularly unique among protein kinases. [004] Mutations in JAK2 are associated with a wide range of human diseases, including cancers such as hematological malignancies (Bader and Meyer, Pharmaceuticals 2022, 15: 160). The gain-of-function V617F mutation in the pseudokinase domain of JAK2 is observed in 70% of patients with myeloproliferative neoplasm (MPN). JAK2 inhibitors are being developed for the Atty. Dckt. No. DFCI 3463.W01WO treatment of MPN, however, all FDA-approved JAK2 inhibitors for MPN are non-selective ATP- competitive inhibitors, which lead to severe side effects. Thus, there is a need for JAK2 pseudokinase selective inhibitor, particularly for the V617F mutant. [005] The development of V617F-selective inhibitors is uniquely challenging because the V617F mutation lies in the pseudokinase domain rather than the kinase domain. Thus, it is likely to require an allosteric approach. One promising target for allosteric inhibitors is the ATP-site of the pseudokinase domain, the TYK2 inhibitor deucravacitinib (BMS-986165) is a precedent for inhibition of a JAK-family kinase via this route and was the first pseudokinase-directed therapeutic FDA-approved for the treatment of autoimmune diseases. [006] Kinase inhibitor JNJ-7706621 has been shown to bind the pseudokinase domain of JAK2 but also binds the kinase domain (Puleo et al. ACS Med. Chem. Lett. 2017, 8:618-621). More selective inhibitors of the pseudokinase domain of JAK2 and the V617F mutant have been developed (Liosi et al. J. Med. Chem. 2020, 63:5324-5340; Liosi et al. J. Med. Chem. 2022, 65:8380-8400; US 2022/0112166 Al and WO 2023/064458 Al). Covalent inhibitors of the pseudokinase domain of JAK2 have also been developed by including an “acrylamide warhead” to modify amino acid cysteine 675 (Cys675) of the JAK2 pseudokinase domain (Henry et al., ACS Med. Chem. Lett. 2022, 13: 1819-1826), but their selectivity for the pseudokinase domain was lower and their affinity for the V617F mutant was not described. Therefore, there is a need for selective inhibitors of the pseudokinase domain of JAK2 that can covalently bind the pseudokinase domain even when the V617F mutation is present. [007] It is known that cancers can become resistant to covalent inhibitors by acquiring mutations at the modification site of the protein, as is seen for the Bruton’s Tyrosine Kinase inhibitor Ibrutinib (Buhimschi et al. Biochemistry 2018, 57:3564-3575) where a PROteolysis TArgeting Chimera (PROTAC) approach was employed to overcome resistance. Therefore, there is a need for inhibitors of the pseudokinase domain of JAK2 that work via different mechanisms or target different residues within the pseudokinase domain of JAK2. Summary [008] Disclosed herein are compounds of formula (I) that inhibit the pseudokinase domain of JAK2. It has been discovered that by including an acrylamide warhead at specific positions and Atty. Dckt. No. DFCI 3463.W01WO with certain linkers, it is possible to modulate the potency and selectivity of the compound within the pseudokinase domain of JAK2. One compound (17) with high affinity and selectivity for the JAK2 pseudokinase domain, was surprisingly shown to result in low levels of cysteine labelling (Table 2). Crystallographic studies confirmed that compound 17 does not form a covalent interaction with Cys675 of the JAK2 pseudokinase domain (data not shown). Mass spectrometry confirmed low cys